Muscarinic agonists

Patent metadata

Field	Value
Publication number	US-12024499-B2
Application number	US-202217672302-A
Country	US
Kind code	B2
Filing date	Feb 15, 2022
Priority date	Aug 3, 2015
Publication date	Jul 2, 2024
Grant date	Jul 2, 2024

Abstract

This invention relates to compounds that are agonists of the muscarinic M1 receptor and/or M4 receptor and which are useful in the treatment of muscarinic M1/M4 receptor mediated diseases. Also provided are pharmaceutical compositions containing the compounds and the therapeutic uses of the compounds. Compounds include those according to formula 1or a salt thereof, wherein q, r, s, Q, R1, R2′, R2″, R3 and R4 are as defined herein.

First claim

The invention claimed is:

1. A method of treating a cognitive disorder, a psychotic disorder, treating or lessening the severity of acute pain, chronic pain, neuropathic pain, or inflammatory pain, treating addiction, or treating a movement disorder in a subject, comprising administering to the subject an effective amount of a compound of formula (1):

or a salt thereof, wherein:
q is 1;
r is 1 or 2;
s is 0 or 1 where the total of r and s is 1 or 2;
Q is an azetidine linked to the adjacent six-membered ring by the nitrogen atom of the azetidine ring;
R 1 is selected from hydrogen, methyl, ethyl, fluorine, oxo, and COOMe;
R 2′ and R 2″ are independently selected from hydrogen, fluorine, and a C 1-6 non-aromatic hydrocarbon group;
R 3 is hydrogen;
R 4 is hydrogen or a C 1-6 non-aromatic hydrocarbon group which is optionally substituted with one to six fluorine atoms; and
the dotted line indicates a single bond.

2. The method according to claim 1 , wherein R 4 is selected from hydrogen and methyl.

3. The method according to claim 1 , wherein the compound is selected from the group consisting of:
Ethyl 2-[4-(3,3-difluoroazetidin-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;
Ethyl 2-{4-[(2R)-2-(methoxycarbonyl)azetidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;
Ethyl 2-[4-(2-oxoazetidin-1-yl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate;
Ethyl 2-{4-[(2S)-2-methyl-4-oxoazetidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;
Ethyl 2-{4-[(2S)-2-ethyl-4-oxoazetidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;
Ethyl 2-{4-[(2R)-2-methyl-4-oxoazetidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate; and
Ethyl 2-{4-[(2R)-2-ethyl-4-oxoazetidin-1-yl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate;
or a salt thereof.

4. The method according to claim 1 , wherein the compound is a pharmaceutically acceptable salt.

5. The method according to claim 1 , wherein the compound is administered to the subject in the form of a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

6. The method according to claim 1 wherein the moiety:

is selected from:

7. The method according to claim 1 wherein the moiety:

is selected from:

Assignees

• Heptares Therapeutics Ltd

Inventors

• Brown Giles Albert
• Cansfield Julie
• Pickworth Mark
• Tehan Benjamin Gerald
• Teobald Barry John

Classifications

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title